Cognex

SIDE EFFECTS

Common Adverse Events Leading to Discontinuation

In clinical trials, approximately 17% of the 2706 patients who received Cognex® (tacrine) and 5% of the 1886 patients who received placebo withdrew permanently because of adverse events. It should be noted that some of the placebo-treated patients were exposed to Cognex® (tacrine) prior to receiving placebo due to the variety of study designs used, including crossover studies. Transaminase elevations were the most common reason for withdrawals during Cognex® (tacrine) treatment (8% of all Cognex® (tacrine) -treated patients, or 212 of 456 patients withdrawn). The controlled clinical trial protocols required that any patient with an ALT/SGPT elevation > 3 X ULN be withdrawn, because of concern about potential hepatotoxicity. Apart from withdrawals due to transaminase elevations, 244 patients (9%) withdrew for adverse events while receiving Cognex® (tacrine) .

Other adverse events that most frequently led to the withdrawal of tacrine-treated patients in clinical trials were nausea and/or vomiting (1.5%), agitation (0.9%), rash (0.7%), anorexia (0.7%), and confusion (0.5%). These adverse events also most frequently led to the withdrawal of placebo-treated patients, although at lower frequencies (0.1% to 0.2%).

Most Frequent Adverse Clinical Events Seen in Association With the Use of
Tacrine

The events identified here are those that occurred at an absolute incidence of at least 5% of patients treated with Cognex® (tacrine) , and at a rate at least 2-fold higher in patients reated with Cognex (tacrine) ®than placebo.

The most common adverse events associated with the use of Cognex® (tacrine) were elevated transaminases, nausea and/or vomiting, diarrhea, dyspepsia, myalgia, anorexia, and ataxia. Of these events, nausea and/or vomiting, diarrhea, dyspepsia, and anorexia appeared to be dose-dependent.

Adverse Events Reported in Controlled Trials

The events cited in the tables below reflect experience gained under closely monitored conditions of clinical trials with a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ.

Table 3 lists treatment-emergent signs and symptoms that occurred in at least
2% of patients with Alzheimer's disease in placebo-controlled trials and who
received the recommended regimen for dose introduction and titration of Cognex®
(see DOSAGE AND ADMINISTRATION).

Other Adverse Events Observed During All Clinical Trials

Cognex® (tacrine) has been administered to 2706 individuals during clinical trials.A total of 1471 patients were treated for at least 3 months, 1137 for at least 6 months, and 773 for at least 1 year. Any untoward reactions that occurred during these trials were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using a modified COSTART dictionary. These categories are used in the listing below. The frequencies represent the proportion of the 2706 individuals exposed to Cognex® (tacrine) who experienced that event while receiving Cognex (tacrine) ®. All adverse events are included except those already listed on the previous table and those COSTART terms too general to be informative. Events are further classified by body system categories and listed using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; and rare adverse events are those occurring in less than 1/1000 patients. These adverse events are not necessarily related to Cognex® (tacrine) treatment. Only rare adverse events deemed to be potentially important are included.

Postintroduction Reports

Voluntary reports of adverse events temporally associated with Cognex® (tacrine) that have been received since market introduction, that are not listed above, and that may have no causal relationship with the drug include the following: pancreatitis, perforated peptic ulcer, and falling.

Theophylline. Coadministration of tacrine with theophylline
increased theophylline elimination half-life and average plasma theophylline
concentrations by approx-i mately 2-fold. Therefore, monitoring of plasma theophylline
concentrations and appropriate reduction of theophylline dose are recommended
in patients receiving tacrine and theophylline concurrently. The effect of theophylline
on tacrine pharmacokinetics has not been assessed.

Cimetidine. Cimetidine increased the Cmax and AUC of tacrine
by approximately 54% and 64%, respectively.

Anticholinergics. Because of its mechanism of action, Cognex® (tacrine)
has the potential to interfere with the activity of anticholinergic medications.

Cholinomimetics and Cholinesterase Inhibitors. A synergistic
effect is expected when Cognex® (tacrine) is given concurrently with succinylcholine
(see WARNINGS), cholinesterase inhibitors, or cholinergic agonists such
as bethanechol.

Fluvoxamine. In a study of 13 healthy, male volunteers, a single
40 mg dose of tacrine added to fluvoxamine 100 mg/day administered at steady-state
was associated with five- and eight-fold increases in tacrine Cmax and AUC,
respectively, compared to the administration of tacrine alone. Five subjects
experienced nausea, vomiting, sweating, and diarrhea following coadministration,
consistent with the cholinergic effects of tacrine.

Other Interactions. Rate and extent of tacrine absorption were
not influenced by the coadministration of an antacid containing magnesium and
aluminum. Tacrine had no major effect on digoxin or diazepam pharmacokinetics
or the anticoagulant activity of warfarin.